The broad goal of the proposed research is to understand molecular mechanisms of dental renewal and the patterning of complex tooth shapes in regenerating dentitions. The phenomenon of tooth renewal is broadly conserved across vertebrates (i.e., humans replace each tooth once early in life) but is absent in the laboratory mouse. Our research benefits from explicit integration of experimental systems (cichlid fishes, mouse, human) and a unique approach translating new molecular and genetic biology from fishes to mammals and back. Experiments described in Specific Aims 1 and 2 of the research plan use molecular and chemical biology to identify and manipulate cell populations and developmental signaling centers responsible for (i) tooth replacement and (ii) replacement tooth shape. We highlight a novel relationship between teeth and taste buds and exploit the strengths of fish, mouse and human systems to test a model of coordinated organ shape/renewal. Experiments under Specific Aim 3 follow from a new differentiation screen in cichlid fishes to discover novel genes controlling vertebrate replacement tooth shape. Because the genes we identify have not been studied in dentitions before, we use gene targeting in the mouse and molecular biology in humans to explore function. Overall, our collaborative approach is designed to solve problems difficult to study in standard lab models because they either do not replace teeth (mouse) or lack oral teeth altogether (zebrafish, chick). The gaps we aim to fill are significant. One in five humans presents with a genetic disorder affecting the dentition and nearly 100% develop problems (e.g, cavities) with age. 30% of people worldwide over the age of 65 lack teeth entirely. Our proposed research will provide answers to the basic question of how regenerating teeth are partitioned into coordinated zones of renewal and differentiation, as new dental organs develop from their predecessors and cusps form on tooth tips. Insights should promote innovative strategies for bio-inspired regenerative dentistry.